Tuberous sclerosis complex (TSC) is an inherited autosomal disorder characterized by the presence of tubers in several organs, including the brain where it may cause seizures, mental retardation, and autism. At the molecular level, mutations of the tumor suppressor genes harmatin and tuberin, also known as tsc1 and tsc2, respectively, have been identified as the cause of TSC. Genetic analyses have revealed that mutations on tuberin are more frequent and responsible for the most severe phenotypes observed in TSC patients. Tuberin and harmatin interact in a heterodimer known as TSC1/TSC2 complex, which functions as a negative regulator of mTOR. mTOR activity is required for protein synthesis-dependent forms of synaptic plasticity, by regulating the phosphorylation of ribosomal S6 kinase (S6K1) and eukaryote initiation factor 4E binding protein (4E-BP), key translation initiation regulators. Evidence suggests that mTOR hyperactivity is a feature of harmatomas syndromes in where tumor suppressor genes, such as tuberin, are mutated. It has been shown that tuberin might be a gene predisposing to autism in TSC patients because it is located in a chromosomal region linked to bipolar disorder, epilepsy and autism.TSC patients have a high rate of autism (17-61%), a behavioral disorder characterized by repetitive stereotyped behaviors, impaired social interaction and communication. The molecular bases of autism in TSC are not completely understood, representing a major challenge for neuroscientists and child neurologists. This proposal is focused on studying the signaling pathways that regulate translation in mice that model TSC. We hypothesize that inhibition of the TSC1/TSC2 complex will result in alterations in hippocampal synaptic plasticity and behavior via upregulated mTOR signaling. To test this hypothesis we are using mice expressing a dominant negative (D/N) tuberin that binds to hamartin, but has a deletion in its carboxyl terminus resulting in increased phosphorylation of S6K1. D/N tuberin is expressed in all tissues, including the brain, making these mice an excellent model to study the impact of TSC on protein synthesis-dependent hippocampal synaptic plasticity, as well as hippocampus-dependent memory, and social behavior. Electrophysiological, behavioral and biochemical analysis will be used to determine whether protein synthesis-dependent synaptic plasticity and mTOR signaling are altered in hippocampal slices, as well as whether these mice are impaired in hippocampus-dependent learning and memory and social interaction. These studies are one of the very few to examine the dysfunction of molecular signaling that control translation and whether they are correlated with altered synaptic plasticity and behavior that would be consistent with autism and mental retardation.